Summary Opioid drug abuse significantly increases the risk and severity of HIV-associated neurocognitive disorders (HANDs). However, the understanding of the interaction between opioids and HIV infection is far from complete. In the current study, we propose to explore the potential of investigating the interaction between opioids and HIV infection by combining two distinct, but complementary, rodent models: 1) the LP-BM5 model, in which a murine retroviral isolate induces a severe immunodeficiency syndrome (murine AIDS, MAIDS) as well as CNS encephalopathy and cognitive deficits in susceptible C57BL/6 (B6) mice; and 2) HIV gp120 transgenic (HIV gp120tg) mice, in which the HIV envelope protein gp120 is produced under the control of the glial fibrillary acidic protein promoter in astrocytes. By combining these two models, we can further examine the effects of morphine on HANDs-like CNS damage in the context of a live viral infection-induced immunodeficiency condition. Further, the type I interferon (IFN) response is a critical anti-viral innate immune mechanism and mediated by IFN? and IFN? through their common receptor, IFNAR. Systemically, HIV-1 can manipulate the host cell type I IFN response in order to establish persistent infection. However, the role of type I IFNs in HANDs is still not well delineated, and the involvement of type I IFNs in HANDs amongst opioid users remains unclear. We propose to further delineate the roles of type I IFNs in co-existing HANDs and morphine use and examine the therapeutic potential of IFN? through the use of the murine models mentioned above. We hypothesize that the lack of an efficient type I IFN response in the hippocampus contributes to morphine-potentiated infection-induced neurological disorders and that by supplying IFN?, we can reduce morphine's detrimental effects and improve neurological outcomes. This central hypothesis will be tested through two Specific Aims. Aim 1. Characterize the type I IFN response in HIVgp120tg mice (using wild type B6 mice as controls) that are subjected to LP-BM5 infection morphine treatment. We will examine HIV-sensitive areas, the hippocampus and the striatum, in comparison to the less sensitive frontal lobe. The interactive effects between infection, gp120, and morphine on the type I IFN response will be evaluated. Aim 2. Determine the therapeutic potential of IFN? in morphine-potentiated neuropathological responses. Through this study, we will establish a unique small animal model system to study HIV/HANDs and the effect of opioid on HANDs. Further, we are advancing towards a novel adjuvant treatment for HANDs in HIV-infected opioid users. It should be noted that IFN? has been successfully used as a disease-modifying treatment for multiple sclerosis. As such, our results could relatively rapidly translate to clinical usage.